The synthesis of new proteins is fundamentally linked with learning and memory. At the molecular level there is strong evidence linking specific types of synaptic activity with the local synthesis of new protein. This grant application proposes the creation of new photochemical tools that will enable researchers to use light to manipulate translation and thereby control where and when proteins are made in neuronal cell culture, in brain slices and ultimately in living animals. The approach taken to the creation of these tools will be chemical synthesis based on the known structures of key components of the biochemical pathways that produce new proteins. Light- activated versions of well-known protein synthesis inhibitors (puromycin, rapamycin, 4E binding proteins) will be created, including reversible versions based on azobenzene photo-switches that can be turned on with light and that turn off in the dark. A second generation of light-activated inhibitors based on photo-active yellow protein/4E binding protein fusions is planned that is genetically-encoded. Genetically-encoded inhibitors can be selectively expressed in particular cells thereby enabling well-defined manipulation of the molecular events involved in learning and memory in whole living animals. Use of these tools thus promises to help uncover how learning and memory occur in living animals at a molecular level. PUBLIC HEALTH RELEVANCE: Numerous mental health problems including post-traumatic stress disorder, epilepsy, obsessive compulsive disorders, or addiction are connected with mis-wiring of the brain, i.e. aberrant synaptic plasticity. Understanding how this works at the molecular level will show the path to effective treatment.